The studies proposed examine the nature, mechanisms and consequences of the interactions of two major environmental pollutants, lead and polychlorinated biphenyls (PCBs), on the heme pathway; and on cytochrome P-450 and the mixed function oxidase system coupled to this heme-protein. Heme and P-450 play a central role in detoxification mechanisms for drugs, hormones, carcinogens and many chemically diverse substances derived from the environment. Lead and PCBs are ubiquitously distributed in the ecosystem of man; produce acute and chronic human diseases; and have potent interactions with the heme-P-450 systems. These interactions are of an inhibitory nature with respect to lead; and of a stimulatory nature with respect to the PCBs. Thus, lead and PCBs serve as excellent model substances for defining in chemical terms, the biological impact of many environment pollutants which inhibit or induce the heme-P-450 complex. Lead and PCB-induced adterations in heme synthesis and in the activities of P-450 coupled enzymes, can be expected to have major pharmacological and toxicological consequences, since the biological actions of drugs, hormones, carcinogens and other chemicals are determined to a signficant degree by the rates at which they are metabolized. These effects of lead and PCBs on the heme-P-450 systems will be explored in detail, utilizing tissue culture techniques, whole animal preparations and clinical investigatios. Special emphasis will be placed on studies involving liver tissues are among the major sites of biological impact of lead and PCBs. Other aspects of the studies proposed will also deal with the role of genetic factors in determining host or tissue responses to the toxic actions of these chemicals. We expect that the information derived from these investigations will enlarge our basic knowledge of the toxicology of environmental pollutants such as lead and PCBs and will have direct relevance to the mechanisms by which such chemicals may produce acute, or chronic human diseases.